Recurrent inflammatory diseases are common skin disorders with high socioeconomic impact. Contact hypersensitivity (CHS) is the prototype recurrent skin inflammatory disease that relays on the interaction of the immune and nervous systems. CHS requires activation of CD4+ and CD8+ effector T cells recognizing haptens present in skin cells. Activation of effector T cells, in CHS requires immunostimulatory skin dendritic cells DCs (sDCs) including epidermal Langerhans cells (LCs) and dermal DCs (DDCs) that transport haptens to skin draining lymph nodes (sDLNs) and activate naive T cells. Thus, inhibition of immunostimulatory DCs would be ideal for the prevention and treatment of skin immune diseases. However, the development of therapies targeting stimulatory sDCs has been extremely difficult due to the complex regulation of the skin immune system. The generation of immunostimulatory DCs requires a pro- inflammatory microenvironment at the moment of DC-antigen (Ag) /hapten interaction. This inflammatory microenvironment is initiated by pro-inflammatory neuropeptides released after skin exposure to Ag/haptens. Substance-P (SP) is the prototype pro-inflammatory neuropeptide which favors cellular immunity by promoting the activation, proliferation and survival of immune cells. In the skin, SP is mainly secreted by sensory C-fibers that interconnect cells with immune function such as LCs, mast cells (MCs), and keratinocytes. SP exerts its immunostimulatory functions by binding the neurokinin 1 receptor (NK1R).We have described that sDCs express functional NK1R and respond to NK1R agonistic binding by inducing Th1 and CTL effector immune responses to protein Ag. Nevertheless, relevant studies addressing the role of locally secreted SP, on the maturation and T cell immunostimulatory function of sDCs during the initiation and recurrence of skin CHS are lacking. We hypothesize that: Pro-inflammatory signaling by SP through the NK1R, at the moment of skin Ag/hapten penetration, promotes the activation of immunostimulatory sDCs and their precursors resulting in the initiation, persistence and recurrence of skin immune diseases which can be limited by local administration of NK1R antagonists. To test our hypothesis we propose the following specific aims: Specific Aim 1: To analyze the mechanisms employed by SP to induce immunostimulatory sDCs during the sensitization phase of CHS. Specific Aim 2: To analyze the role and mechanisms employed by SP in T cell responses, stimulated by sDCs during sensitization, elicitation and resolution of CHS. Specific Aim 3: To analyze, the possibility of using local administration of specific NK1R antagonists to suppress CHS by down-regulating the T cell-stimulatory function of sDCs and their precursors. PUBLIC HEALTH RELEVANCE: Recurrent inflammatory skin diseases are common disorders with high socioeconomic impact. Contact hypersensitivity (CHS), is the prototype recurrent skin inflammatory disease that depends on the interaction of the immune and nervous systems. The initiation and recurrence of CHS is triggered by pro-inflammatory neuropeptides released locally in the skin at the moment of antigen exposure. Substance-P (SP), a potent neuropeptide, is responsible for the initiation and recurrence of skin inflammation and for the activation of the population of dendritic cells, the most potent skin resident antigen presenting cells. In this application we propose to inhibit the effects of SP by blocking specifically its functional neurokinin-1 receptor (NK1R) by delivering synthetic non-peptide NK1R antagonists locally in the skin at the moment of Ag exposure. This will be accomplished using both murine, and a unique model of human skin explants that we have developed to facilitate translation to clinical trials. The studies we propose have the potential to overcome recurrent skin inflammatory and immune diseases and they include translational preclinical models designed as a direct prelude to human clinical trials.